This relates to total parenteral nutrition of patients with liver disease or septicemia. It is particularly concerned with providing such nutrition via lipid emulsions. Lipid emulsions for parenteral nutrition are available commercially or can be manufactured in accordance with known processes. Generally, such emulsions have been made using the triglycerides of long chain fatty acids (LCTs). LCTs are obtained conventionally from soybean or safflower oil. Long chain fatty acids are fatty acids having 14 or more carbon atoms, usually 16 or 18 carbon atoms.
More recently, lipid emulsions which contain triglycerides of medium chain fatty acids (MCTs) have become available. MCTs are triglyceride esters of fatty acids which contain a preponderance of C.sub.8 and C.sub.10 fatty acids (caprylic and capric acid, respectively). Emulsions of this type are disclosed in European Patent Application No. 0071995 and Eckart et al., "J. Parenteral and Enteral Nutrition" 4(4):360-366 (1980). The above cited European Patent Application discloses an isotonic LCT/MCT emulsion for parenteral use, which contains a fat content of 3 to 30%, an LCT/MCT ratio between 4/1 and 1/4, a physiologically unobjectionable polyhydric alcohol and egg phosphatide as emulsifier.
Early studies involving enteral administration of MCT emulsions to animals and man indicated that MCTs are handled by a physiological pathway other than the one known for LCTs. In-depth studies revealed that MCTs are hydrolyzed to free fatty acids in the intestinal lumen at a rate five times faster than the hydrolysis rate for LCTs. Further, these MCT-derived fatty acids are absorbed by the intestinal cell at a rate twice the absorption rate of LCT-derived fatty acids. The most striking difference between MCT and LCT was shown to be the mechanism of transport to sites of utilization and, as a result, their predominant mode of utilization. MCT-derived fatty acids pass through the intestinal epithelial cell without reesterification to MCT. They then enter the portal vein, bind to albumin, and are transported in this bound form in the bloodstream. LCT-derived fatty acids, on the other hand, after absorption are reesterified in intestinal cells to form LCT and packaged with protein and phospholipids to form lipid particles (chylomicrons) that enter the lymph system and, later, the circulatory system for distribution to the tissues of utilization.
In comparison to LCTs, MCTs are much more readily utilized for caloric energy, but are less effectively incorporated into tissue lipids. MCTs, when administered orally, are believed to be metabolized primarily in the liver, while LCTs are metabolized throughout the body (Scheig, R. In: Medium Chain Triglycerides, J. R. Senior, Ed. pp 39-49 [1968]).
Liver disease as this term is used herein means a primary or secondary disorder of the liver parenchyma that results in reduced hepatic function. The etiology of the disease may include but not be limited to any one of the following common disorders: Alcoholic cirrhosis, acute hepatocellular damage secondary to drug abuse or poisoning, genetic deficiencies such as tyrosinosis, trauma to the liver, hepatitis, primary biliary cirrhosis, liver abscess, Budd-Chiari syndrome, Wilson's disease, or primary or secondary liver neoplasms. Clinically, hepatic dysfunction is diagnosed by increases in liver function tests such as serum glutamate-oxaloacetate transaminase, serum glutamate-pyruvate transaminase and bilirubin, reductions in indocyanin green or bromosulphopthalein clearance, tissue biopsy, and/or neurological manifestations such as encephalopathy. Liver disease as defined herein excludes the subclinically mild and reversible hepatic dysfunction induced by parenteral nutrition (Eckart et al. Ibid).
Patients with septicemia include patients having subclinical septicemia or susceptibility to septicemia. Patients in this group include patients recuperating from abdominal surgery, patients with respiratory diseases and those with active infections such as abcesses or infected wounds.
Intravenous calorie intake in liver diseased patients is hampered by chronic carbohydrate and fluid intolerance. In addition, current LCT emulsions, although calorically dense, are contraindicated in liver disease because liver dysfunction is frequently associated with an impaired ability to metabolize LCT. A need exists for an intravenous calorie source for liver diseased patients that does not exhibit the disadvantages of available calorie sources.
MCTs have been included in oral formulations for the nutrition of stressed (including liver disease) patients. An example is the Travasorb Hepatic formulation sold by Travenol Laboratories, Inc. The doses of MCT to be delivered with such formulations have been low, however, on the order of about 0.2 mg MCT/Kg body weight (BW)/min. when following the instructions for use. MCTs are added to these nutrient formulations because they are believed necessary to circumvent the maladsorption of LCTs that accompanies deficient bile secretion by diseased livers. However, the low doses were believed mandated by the prevalent belief in the art that MCTs are harmful to liver diseased patients. See, for example, N. Greenberger et al. "Ann. Intern. Med." 66(4):727-734 (1967), who state that "it will be important to withhold MCT therapy from patients with decompensated cirrhosis until more is known about the effects of MCT therapy on such patients." (Id at p. 732). In part, this contraindication is based on the role of the liver as the primary site of medium chain fatty acid metabolism. The dysfunctional liver might not be expected to metabolize these fatty acids at a rate sufficient to avoid the observed effects of excess fatty acids in the blood: Somnolence, vomiting and even death. In addition, the narcotic effect of MCTs could be expected to exacerbate any tendency in liver diseased patients towards encephalopathy. Thus, MCTs have not been considered appropriate for providing a substantial percentage of the calorie needs of liver diseased patients.
We now have discovered that MCTs can be parenterally administered to recipients with liver disease or septicemia, and in dosages heretofore believed to be potentially hazardous, without toxic side effects. We have found that MCTs can supply nutritionally adequate calories to such patients without resulting in the liver fatty deposits or the reductions in the efficacy of the reticuloendothelial system (RES) noted when supplying LCTs as a significant calorie source.